Physical inactivity is a major risk factor for cardiovascular disease, the leading cause of death in the United States. Several inactivity-related cardiovascular diseases such as obesity and hypertension are characterized by increased blood pressure and activity of the sympathetic nervous system. The sympathetic nervous system is primarily controlled by an important brain region known as the rostral ventrolateral medulla (RVLM). Despite increasing rates of physical inactivity and cardiovascular disease in our society, there is very little known about how this brain region changes over time in individuals that are physically active versus those that remain sedentary. This lack of knowledge about how physical inactivity may contribute to cardiovascular disease by effects on this important brain region represents a fundamental gap in our field. This research proposal will study the changes that occur over time in regulation of the cardiovascular system by the RVLM in sedentary versus physically active animals. Recent data from the Sponsor's laboratory has shown that the response to activation of the RVLM is enhanced in sedentary relative to physically active animals. Over activity of the RVLM could be a key contributor to the overall elevation in sympathetic nervous system activity that is seen in many cardiovascular diseases. The central hypothesis of this proposal is that physical inactivity enhances, and physical activity reduces sympathetic activation produced by the RVLM. This central hypothesis is based on strong preliminary and published data from the Sponsor's laboratory. This project will determine central nervous system mechanisms by which a sedentary lifestyle may contribute to cardiovascular disease. This proposal utilizes an experimental design that will examine time-dependent changes that occur under sedentary conditions. Active animals will be considered the healthy control, and sedentary animals the disease model. As a whole, this proposal addresses a fundamental question regarding the effect of physical inactivity on regulation of sympathetic nervous system activity by the brain stem and is a key step in understanding the contribution of physical inactivity to cardiovascular disease.